Overview: What every practitioner needs to know

Are you sure your patient has adrenal insufficiency? What are the typical findings for this disease?

Thomas Addison initially described a syndrome of weakness and hyperpigmentation associated with adrenal gland destruction in 1855. Adrenal insufficiency is caused by either primary adrenal failure or by secondary causes involving impairment of the hypothalamic -pituitary -corticotropic axis. It is a rare disease and is life threatening if untreated. The main presenting symptoms such as fatigue are non-specific, hence diagnosis is often delayed. It primarily presents as an adrenal crisis which is life threatening and requires prompt therapeutic management including fluid resuscitation and stress dose hydrocortisone administration.

Patients with acute adrenal insufficiency (AI) or Addisonian crisis generally present with acute dehydration, hypotension, hypoglycemia, shock, altered mental status or sudden death. Hypoglycemia is most common in young children. Altered mental status may occur at any age.

Patients with secondary AI, usually have signs of other pituitary hormone deficiencies such as growth failure, delayed puberty, secondary hypothyroidism and/or diabetes insipidus. There may be a history of recent pharmacologic glucocorticoid therapy.

Hyperpigmentation, hyperkalemia and metabolic acidosis were found to be common (>90% of the cases) in primary AI when hypoglycemia was a prominent finding in secondary AI.

What other disease/condition shares some of these symptoms?

Chronic AI can present with ill-defined fatigue and generalized muscular weakness. These are very non-specific and can mimic a gastrointestinal disorder like celiac disease or a psychiatric illness, especially depression.

Although a list of hyponatremia etiology is extensive, when hyponatremia occurs simultaneously with hyperkalemia, acidosis and volume depletion, there are only few conditions explainable by this combination. These are typically associated with aldosterone deficiency (from adrenal gland insults or enzymatic defect) or lack of aldosterone action (resistance or blockage from medications).

Type 4 renal tubular acidosis is characterised as a hypoaldosterone state, and should be considered in any patient with persistent hyperkalemia in whom there is no obvious cause such as renal failure or the use of potassium supplements or a potassium-sparing diuretic. In adults, hypoaldosteronism is usually associated with a mild metabolic acidosis with a normal anion gap (i.e., a hyperchloremic acidosis).

What causes this disease to develop at this time?

AI is categorized as either primary versus secondary, or congenital versus acquired. In primary AI, there is a combined deficiency of glucocorticoids, mineralocorticoids and adrenal androgens, and in some cases, associates with adrenal medulla deficiency. In secondary AI, there is a lack of corticotropin releasing hormone (CRH) secretion from the hypothalamus and/or adrenocorticotropic hormone (ACTH) secretion from the pituitary. This results in hypofunction of adrenal cortex, however the mineralocorticoid function is preserved. It is known that mineralocorticoid release by the zona glomerulosa of the adrenal is determined by the renin-angiotensin system, with acute modulation of lower magnitude also by ACTH .

In the kidney, increased cortisol can act on the distal nephron via MR to cause sodium retention and potassium loss. Glucocorticoids can increase free water clearance by antagonizing vasopressin action, therefore hyponatremia can be seen in patients with glucocorticoid deficiency.

Brain is another important target tissue for glucocorticoids, this may explain the clinical observation of depression, apathy and lethargy in patients with deficient glucocorticoids. Mineralocorticoids, on the other hand, have a more restricted role, principally stimulation of epithelial sodium transport in the distal nephron, distal colon, and salivary glands. Clinical symptoms of mineralocorticoid deficiency are secondary to volume depletion and electrolyte abnormalities.

Etiology of primary AI is divided into three categories:

1. Adrenal dysgenesis/ hypoplasia and unresponsiveness of ACTH: This refers to congenital adrenal structural developmental defects. Multiple genes are essential for normal development and subsequent function of the adrenal cortex. Mutations in any of these genes can lead to adrenal dygenesis.

Adrenal hypoplasia congenital (AHC) is a rare familial condition in which adrenal cortex has arrested development, occurring in about 1 of 12,500 births. Mutations in the dosage sensitive sex reversal adrenal hypoplasia gene 1 (DAX-1) can cause X-linked form of congenital adrenal hypoplasia, which typically presents in males with life threatening adrenal crisis in the newborn period and hypogonadotropic hypogonadism later in adolescence. In this disorder, the adrenal androgen secretion is not increased and the response of cortisol and its precursors to ACTH stimulation is blunted or absent.

To date, another identified transcription factor pivotal for adrenal development is SF1. It also plays a critical role in male gonadal differentiation. Clinical spectrum of loss of function in SF1 ranged from AI, variable degrees of undervirilization of 46, XY individual, absence of testis and progressive Sertoli defect.

Familial glucocorticoid deficiency (FGD): Mutations of the ACTH receptor and its related genes, AAAS, result in familial glucocorticoid deficiency (FGD). It is an autosomal recessive disorder of ACTH resistance in which cortisol and androgen secretion are both deficient, while aldosterone production is typically normal. FGD usually presents in childhood with hyperpigmentation, weakness, hypoglycemia and seizures. In the instance that adrenocortical deficiency occurs along with other presentations such as achalasia and alacrimia, the syndrome is called Allgrove or triple A syndrome.

Among these, CAH owing to defective 21 hydroxylase is the most common cause of primary AI in early infancy. The most common subtype results from complete enzyme deficiency giving rise to defective production of both glucocorticoids and mineralocorticoids, and presents with severe salt wasting adrenal crisis in the first 2 to 3 weeks after birth. Furthermore, accumulated steroid precursors proximal to the enzymatic block are shunted into the androgen synthesis pathway, leading to overproduction of adrenal androgens. This causes virilization in the female fetus and becomes the most common cause of ambiguous genitalia in female infants (further information, please see CAH chapter).

3. Adrenal destruction: Autoimmune destruction of the adrenal cortex is the most common cause of Addison disease beyond infancy, but infections, metabolic and infiltrative or metastatic diseases, and drugs can be identified as other causes. Autoimmune damage to the adrenal gland is maybe isolated or occurs in the context of autoimmune polyendocrine syndrome (APS type 1 or 2). APS-1 has an early childhood onset and consists of a triad of hypoparathyroidism, chronic mucocutaneous candidiasis and Addison disease. APS 2 has an adult onset, typically in the fourth decade of life and is defined by Addison disease, thyroiditis and diabetes mellitus.

Adrenal destruction is also a feature of an X-linked recessive disorder of metabolism of long-chain fatty acids characterized by progressive neurologic dysfunction and primary AI. The combination of the two possible phenotypes, adrenoleukodystropy and adrenomyeloneuropathy, affects approximately 1 in 20,000 males and accounts for as many as 10% of all cases of AI in children and young men. In this disease, a defective beta oxidation in peroxisomes leads to accumulation of very long chain fatty acid in the adrenal cortex, among other sites.

AI may present in infancy with acute adrenal crisis, often preceding the neurological symptoms. Other manifestations of adrenoleukodystropy begin in infancy or childhood with weakness and spasticity and the disorder progresses rapidly to dementia, blindness and quadriparesis. Adrenomyeloneuropathy begins in adolescence or early adulthood with weakness, spasticity, and distal polyneuropathy but is milder and progresses more slowly.

Infection remains an important cause of adrenal failure. Historically, tuberculosis was the leading cause of Addison disease. It still remains the leading cause in developing countries. Meningococcal infection can lead to bilateral adrenal hemorrhage, known as Waterhouse-Friderichsen syndrome. Chronic infections with fungus, cytomegalovirus, human immunodeficiency virus can lead to adrenal failure.

Adrenal hemorrhage is also seen as a result of birth traumas related to difficult deliveries, sepsis, coagulopathy, traumatic shock and ischemic disorders. Hemorrhage may lead to AI, which in turn has a manifestation of neonatal hypoglycemia, hypotension, hypothermia, apnea or shock. Other infections in the neonate that have been associated with AI are herpes virus (HSV), pseudomonas aeruginosa, bacteroides, HSV 6, echo virus Types 11 and 6. Septic shock in newborns may result in adrenal hemorrhage with rhabdomyolysis and renal insufficiency.

Etiologies of secondary AI are summarized below. Basically, they are consequences of any insult at the level of hypothalamic-pituitary areas.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Hyponatremia and hyperkalemia are common in primary AI because of deficient aldosterone secretion. Hypoglycemia is a feature of both primary and secondary AI. Hyponatremia may also be seen in secondary AI because of water retention from lack of cortisol to antagonize the effect of vasopressin secretion.

Primary glucocorticoid deficiency is confirmed by an elevated plasma ACTH concentration (frequently >100 pg/ml or 22 pmol/L) and a low serum cortisol concentration (generally < 10 mcg/dl or 275.9 nmol/L). When the diagnosis is in doubt, standard ACTH stimulation test (250 µg intravenous dose) should be performed. A normal response is a rise in serum cortisol concentration after 60 minutes to a peak of 18 mcg/dl (496.6 nmol/L) or more. A subnormal response confirms the diagnosis of AI. If an enzymatic defect in steroidogenesis is suspected, an ACTH stimulation test with complete adrenal biochemical profile (cortisol, aldosterone, androgens and their precursor hormones) is performed to permit additional analysis of precursors:product ratio.

Mineralocorticoid deficiency is usually present exclusively in primary AI. This can be explained by the fact that renin-angiotensin system primarily controls aldosterone production; ACTH plays a minor role in this feedback loop. Therefore, in patients with hypothalamic-pituitary disease, aldosterone secretion is usually preserved. When mineralocorticoid deficiency is present, aldosterone is relatively low in the face of elevated renin.

The diagnosis of secondary AI is associated with low blood cortisol and ACTH levels. 8 am cortisol level of <3 µg/dl is suggestive of diagnosis and a value of =18 µg/dl rules out the diagnosis of AI. The low dose (1 µg intravenously) ACTH test seems to be more sensitive than the standard dose in the cases of secondary AI. A recent meta-analysis comparing those two ACTH tests suggested the superiority of low dose corticotrophin test in detecting secondary AI.

Would imaging studies be helpful? If so, which ones?

Adrenal imaging (Computed tomography [CT] or magnetic resonance imaging[MRI]) can be done to look for adrenal hemorrhage in cases of primary AI. Bilateral adrenal calcifications are considered pathognomonic for Wolman’s disease which is a rare genetic cause of adrenal failure.

Imaging of pituitary- hypothalamic region (MRI) should be obtained to exclude hypothalamic pituitary mass lesions as an etiology in cases of secondary AI. Pituitary adenomas are the most common; craniopharyngioma are rare but may present at any age. Very rare causes include meningiomas, metastases and infiltration.

Confirming the diagnosis

Two approaches to a patient with AI are shown here. The first approach (See Figure 1) is for patients who are suspected to have AI in general. When primary AI is likely, the second approach (See Figure 2) is more suitable.

If you are able to confirm that the patient has adrenal insufficiency, what treatment should be initiated?

Acute AI is a medical emergency. Management involves fluid resuscitation with a 20 ml/kg bolus of normal saline, repeated fluid boluses may be needed. Replacement of fluid losses should be continued with isotonic crystalloid solutions containing dextrose (typically 5% dextrose with normal saline).

Stress doses of hydrocortisone (100 mg/m2/day) are vital as rescue therapy and should be administered as early as possible, concomitant with intravenous fluid treatment. The initial hydrocortisone (Solucortef) administration may be given intramuscularly en route to the emergency department. The recommended dose of Solucortef is 25 mg IM for an infant, 50 mg IM for a child and 100 mg IM for an adult. Once a venous access is available, subsequent hydrocortisone doses should be given intravenously. In our institution, hydrocortisone is given as an intermittent bolus every 4 to 6 hours. In some places, the preferred method is a continuous intravenous drip.

Central venous access and vasopressors, along with higher glucose concentrations, are maybe required in profoundly ill patients. An ECG can be done to evaluate hyperkalemia. With mild to moderate hyperkalemia, there is development of peaked T waves. Severe hyperkalemia results in a widening of the QRS complex. Life threatening hyperkalemia may require additional therapy with sodium polystyrene, intravenous calcium, insulin and bicarbonate.

Long-term treatment of Addison disease requires glucocorticoid and mineralocorticoid replacement, with careful attention to coexisting hormonal deficiencies, particularly hypothyroidism. Hypothyroidism is seen mostly in secondary AI, but even autoimmune primary AI can co-exist with hypothyroidism. Treating hypothyroidism without correcting AI may precipitate a severe adrenal crisis since normalization of thyroid hormones will accelerate cortisol breakdown and unmask hypocortisolism, therefore possibly aggravating signs and symptoms of hypocortisolism.

Glucocorticoid replacement: Physiological daily cortisol production rates vary between 5 and 10 mg/m2. For children, the preferred cortisol replacement is oral hydrocortisone (9-12 mg/m2/day) divided into 3 doses because of its short half- life and minimal suppression of growth. The major part of daily replacement dose is usually taken in the morning. Starting from very low cortisol concentrations, the morning dose becomes rapidly available within 30-60 minutes. Preparations like prednisone or dexamethasone which have longer half-lives can be used if needed to facilitate adherence and are used after growth is complete, since these preparations have an effect of growth. Normal growth rate, sense of well-being, and good energy level indicate adequate replacement therapy.

It is important to consider concurrent medications such as drugs which increase hepatic glucocorticoid metabolism by CYP3A4 induction (for example; rifampicin, mitotane, phenytoin, oxcarbazepine, carbamazepine, phenobarbitone, topiramate), which results in increased 6 ß-hydroxylation and hence cortisol inactivation. This may require a 2 to 3 fold increase in glucocorticoid dose to sustain the same physiologic effect. Conversely, the intake of drugs inhibiting CYP3A4 ( for example; anti-retro vital agents) would require a reduction of glucocorticoid replacement dose. Pregnancy is associated with increased cortisol-binding globulin and thus total cortisol. During the last trimester, free cortisol increases which requires a 30%-50% increase in hydrocortisone dose in patients who require glucocorticoid treatment.

Mineralocorticoid Replacement: Patients with primary AI require mineralocorticoid replacement. Fludrocortisone is given at a dose of 0.1 to 0.2 mg/day. In newborns and infants, sodium chloride supplementation may be required. In older children and adults, dietary intake is typically adequate without the need for further supplementation. Monitoring includes serum electrolytes, plasma renin (which should be maintained at the upper normal range). If essential hypertension develops, mineralocorticoid dose should be slightly reduced.

What are the adverse effects associated with each treatment option?

Inadequate dose of glucocorticoid may lead to symptoms of fatigue, weakness, weight loss and nausea. It can also bring about increased risk of incipient crisis and severe impairment of well being. Conversely, chronic over replacement is associated with substantial morbidity, including impaired glucose tolerance, obesity and osteoporosis.

What are the possible outcomes of adrenal insufficiency?

If untreated, it can lead to severe morbidity and mortality.

What causes this disease and how frequent is it?

Primary and secondary AI (excluding critical illness AI and AI secondary to acute interruption of chronic glucocorticoid therapy) are rare diseases, affecting less than 0.1% of the population. The incidence of CAH is estimated to be 1 in 10,000 to 18,000 live births.

How do these pathogens/genes/exposures cause this disease?

The presence of circulating auto antibodies to endocrine antigens is a serologic characteristic of Addison’s disease. After the appearance of antibodies to adrenal cortex and /or 21 hydroxylase (21 OHA), the first evidence of AI is usually an increase in renin after patients have been recumbent for more than 0.5 h. This is due to failing zona glomerulosa function leading to salt loss and inappropriately low aldosterone concentrations. Zona fasciculata dysfunction can become evident months to years later, first by raised afternoon serum ACTH levels, then by decreasing serum cortisol responses to ACTH stimulation, and finally by decreasing basal serum cortisol concentrations and the appearance of symptoms.

Other clinical manifestations that might help with diagnosis and management

In chronic primary AI, “muddy” hyperpigmentation may be noted because of elevation of pro-opiomelanocortin and melanocyte stimulating hormones. The increased skin pigmentation is seen in the areolae, genitalia, scars and moles. Areas exposed to sun (palmer creases, axillae) often are hyperpigmented. The patient also may have pigmentary lines in the gums. In rare cases, a defect of melanocyte response can result in absence of hyperpigmentation. Salt craving is common in chronic primary AI. The patients may demonstrate orthostatic hypotension. Some patients also may loose pubic and axillary hair.

What complications might you expect from the disease or treatment of the disease?

Are additional laboratory studies available; even some that are not widely available?

Mutation analysis of CYP21A2 to confirm the diagnosis of 21 hydroxylase CAH is commercially available. Also mutation analysis is available to confirm other forms of CAH. Adrenal auto-antibodies are positive in autoimmune Addison disease. The possibility of other endocrine gland dysfunction should be evaluated by measuring serum calcium, phosphorus, intact PTH, glucose and TSH.

Hypogonadism should be investigated in post-menarchal female adolescents presenting with oligomenorrhea or amenorrhea by measuring serum gonadotropins. Possible hypogonadism in males is evaluated by measuring serum testosterone and luteinizing hormone. DNA analysis for genes including DAX 1, SF1, AAAS (ALD gene), AIRE, ACTHR, HSD3B2 may be appropriate for undervirilized 46, XY with AI. Analysis of very long chain fatty acid can be obtained for the diagnosis of X linked adrenoleukodystrophy. ABCD1 gene mutations can be obtained which encode for the peroxismal adrenoleukodystrophy protein.

How can adrenal insufficiency be prevented?

Acute AI is a life threatening condition that develops as a result of inadequate adrenal steroid production not matching increasing demands during stress (for example, during infection). Adrenal crisis in patients with known chronic adrenal failure is best prevented by structured and repeated patient education focusing on stress dose glucocorticoid adjustment. Written instructions to the patient should be provided regarding how and when to increase glucocorticoid therapy. These instructions should be reviewed at each visit so that the dose can be appropriately increased as the child grows.

Every patient should wear a medical bracelet or necklace that has emergency medical information attached. The family should be instructed on the use of intramuscular hydrocortisone sodium succinate in case of vomiting or severe stress. In children prone to hypoglycemia, the family should be trained in monitoring and management of glycemic excursion.

In times of stress, an increased dose of glucocorticoids is required to mirror normal physiologic response. Doubling or tripling the daily maintenance dose of oral hydrocortisone for mild stress generally is adequate. Emergency injectable hydrocortisone must be available in case of vomiting or inability to tolerate oral intake. In conditions of severe stress such as major surgery, intensive trauma and sepsis, treatment should be similar to that for adrenal crisis.

Mild stress such as immunization, uncomplicated viral illnesses and upper respiratory tract infections may not require use of a stress dose regimen. More severe stress such as illnesses with fever = 38 degrees C, vomiting, diarrhea, inadequate oral intake, lethargy, surgery, trauma, dental work and large burns should be treated with increased glucocorticoid doses to prevent adrenal crisis. A common recommendation is to treat most stresses that require increased doses with hydrocortisone 30 to 50 mg/m2/day (triple dose) divided into 3-4 doses over the day. The most severe stresses such as major surgery or sepsis is treated with glucocorticoid doses up to 100 mg/m2/day divided every 6 hours intravenously.

Table I gives the perioperative guideline used at our institution to stress dose patients with CAH or other AI diagnoses prior to a procedure. The glucocorticoid dose can be quickly reduced to chronic replacement doses, provided no postoperative complications have occurred. As a rule, oral replacement can be used as soon as the patient is able and allowed to take orally.

Pharmacological administration of synthetic glucocorticoid (at much higher dose and more potent GC) leads to feedback inhibition of endogenous cortisol secretion and eventually adrenal atrophy. Moreover, chronic exogenous glucocorticoid therapy may lead to insufficient capacity of the adrenals to respond to stress, putting the patient at risk of acute adrenal crisis. This is seen in patients with inflammatory disorders on prednisone or dexamethasone for many months. Hence, careful weaning of corticosteroids is recommended.

See Figure 3 for guideline for weaning regimen of exogenous steroids. The purposes of tapering dose of GC are to avoid flaring up of the underlying condition (at pharmacologic dose) and to allow recovery of HPA axis. Once the weaning dose approaches physiologic dose (equivalent of hydrocortisone dose of 10-15 mg/m2/day), the focus is switched to facilitating HPA axis recovery. It is expected that endogenous cortisol secretion, under the patient's own ACTH control, will take place during the off days in alternate day approach.

Figure 3.

Suggested approach to tapering steroids

In everyday approach, supplemental hydrocortisone is slowly decreased to allow recovery of ACTH secertion and thereby endogenous cortisol production to rise to normal levels. During the weaning process when the patient is on or below physiological dosing and there is an acute stress such as illness or fever, it is recommended to go back to stress dosing and then resume the weaning process.

Ongoing controversies regarding etiology, diagnosis, treatment

There is a controversy regarding treatment with glucocorticoids in patients with "relative AI". These are the patients with acute (non adrenal or pituitary) critical illness thought to secrete less cortisol than expected during acute stress and may benefit from pharmacologic glucocorticoid therapy. However, many of these acutely ill patients are hypoalbuminemic, and therefore are also making less cortisol binding globulin, so their free cortisol levels may be normal even when total cortisol levels are "relatively" low.

In AI patients, adrenal androgen replacement is being studies in adults, but limited data is available for children and adolescents. DHEA has been shown to significantly enhance well-being, mood and subjective health status in women with primary and secondary AI and also recently in children and adolescents with adrenal failure. DHEA has been shown to exert beneficial effects on subjective health status and energy levels not only in women but also in men with primary AI including significant effects on bone mineral density.

In adult women with signs of androgen deficiency such as dry, itchy skin and loss of libido, a single dose of DHEA 25-50 mg in recommended in the morning. The latest and largest DHEA replacement trial in adults with Addison’s disease indicated positive effects on bone metabolism but little effects on HRQoL in the group. Whether a thrice daily glucocorticoid regimen should be preferred over twice daily administration is not clear because well designed and appropriately powered studies are lacking. Timed release hydrocortisone tablets and continuous subcutaneous hydrocortisone infusion are promising new treatment modalities which are under investigation.

Controversy also exists regarding the use of physiologic stress doses of hydrocortisone in the hypotensive infant in the NICU. Recent studies have demonstrated low circulating level of cortisol in preterm infants under stress, suggesting that the underlying pathophysiology of systemic hypotension may be associated with an immature hypothalamic-pituitary-adrenal (HPA) axis secondary to intermediate enzyme deficiency and decreased capacity to synthesize cortisol. Adrenocortical insufficiency secondary to immature HPA axis, however, is transient. In the majority of cases, both pituitary and adrenal glands are able to respond adequately to exogenous stimulation by day 14 of life, although in some extremely premature infants, the inadequate adrenocortical response may persist into the third week.

As the transient functional abnormality may contribute to the development of systemic hypotension in preterm newborns, some authorities recommend treating these infants with steroids to replace the physiologic deficient hormone during the acute phase. On the other hand, studies in animal models and epidemiology studies in human raised the concerns of potential adverse effects of steroids on the developing brain. The balance of potential risks and benefits need to be considered until more information is available.